Field of the Disclosed Subject Matter
The presently disclosed subject matter is related to the coating of interventional medical devices, and particularly coating of therapeutic agents on an expandable member of a medical device. More particularly, the presently disclosed subject matter relates to a method for performing a plasma treatment to a balloon prior to applying a therapeutic agent on the balloon.
Description of Related Subject Matter
Atherosclerosis is a syndrome affecting arterial blood vessels. It is characterized by a chronic inflammatory response in the walls of arteries, which is in large part due to the accumulation of lipid, macrophages, foam cells and the formation of plaque in the arterial wall. Atherosclerosis is commonly referred to as hardening of the arteries, although the pathophysiology of the disease manifests itself with several different types of lesions ranging from fibrotic to lipid laden to calcified. Angioplasty is a vascular interventional technique involving mechanically widening an obstructed blood vessel, typically caused by atherosclerosis.
During angioplasty, a catheter having a folded balloon is inserted into the vasculature of the patient and is passed to the narrowed location of the blood vessel at which point the balloon is inflated to the desired size by fluid pressure. Percutaneous coronary intervention (PCI), commonly known as coronary angioplasty, is a therapeutic procedure to treat the stenotic regions in the coronary arteries of the heart, often found in coronary heart disease. In contrast, peripheral angioplasty, commonly known as percutaneous transluminal angioplasty (PTA), generally refers to the use of mechanical widening of blood vessels other than the coronary arteries. PTA is most commonly used to treat narrowing of the leg arteries, especially, the iliac, external iliac, superficial femoral and popliteal arteries, and arteries more distal to these in the lower limbs. PTA can also treat narrowing of carotid and renal arteries, veins, and other blood vessels.
Although the blood vessel is often successfully widened by angioplasty, sometimes the treated region of the blood vessel undergoes vasospasm, or abrupt closure after balloon inflation or dilatation, causing the blood vessel to collapse after the balloon is deflated or shortly thereafter. One solution to such collapse is stenting the blood vessel to prevent collapse. Dissection, or perforation, of the blood vessel is another complication of angioplasty, which can be improved by stenting. A stent is a device, typically a metal tube or scaffold that is inserted into the blood vessel after, or concurrently with angioplasty, to hold the blood vessel open.
While the advent of stents eliminated many of the complications of abrupt vessel closure after angioplasty procedures, within about six months of stenting a re-narrowing of the blood vessel can form, a condition known as restenosis. Restenosis was discovered to be a response to the injury of the angioplasty procedure and is characterized by a growth of smooth muscle cells and extracellular matrix—analogous to a scar forming over an injury. To address this condition, drug eluting stents were developed to reduce the reoccurrence of blood vessel narrowing after stent implantation. A drug eluting stent is a stent that has been coated with a drug, often in a polymeric carrier, that is known to interfere with the process of re-narrowing of the blood vessel (restenosis). Examples of various known drug eluting stents are disclosed in U.S. Pat. Nos. 5,649,977; 5,464,650; 5,591,227, 7,378,105; 7,445,792; 7,335,227, all of which are hereby incorporated by reference in their entirety. However, a drawback of drug eluting stents is a condition known as late stent thrombosis. This is an event where a blood clot forms inside the stent, which can occlude blood flow.
Drug coated balloons are believed to be a viable alternative to drug eluting stents in the treatment of atherosclerotic lesions. In a study which evaluated restenosis, and the rate of major adverse cardiac events such as heart attack, bypass, repeat stenosis, or death in patients treated with drug coated balloons and drug eluting stents, the patients treated with drug coated balloons experienced only 3.7% restenosis and 4.8% MACE (material adverse coronary events) as compared to patients treated with drug eluting stents, in which restenosis was 20.8 percent and 22.0 percent MACE rate. (See, PEPCAD II study, Rotenburg, Germany).
A drug coated balloon is a unique drug-device combination product. In addition to performing a dilatation function, it must deliver a therapeutic level of drug to the vascular tissue during an inflation that lasts only thirty seconds to a few minutes. This rapid transfer of drug requires coatings that release a large fraction of drug during the balloon inflation. While there are many potential mechanisms of drug transfer for a drug coated balloon, the primary ones are: transfer of coating to the vessel wall with subsequent diffusion of drug into tissue; insertion of coating into tissues or fissures in the vessel wall produced by the dilatation; pressing the coating against the vessel wall, the drug dissolving into a thin liquid film to create a drug saturated boundary layer, and this dissolved drug diffusing into the tissue; and drug dissolving the entire time the balloon is near, or expanded against, the vessel wall and this dissolved drug diffusing into the tissue.
However, drug coated balloons present certain unique challenges. For example, the drug carried by the balloon needs to remain on the balloon during delivery to the lesion site, and released from the balloon surface to the blood vessel wall when the balloon is expanded inside the blood vessel. For coronary procedures, the balloon is typically inflated for less than one minute, typically about thirty seconds. The balloon inflation time can be longer for a peripheral procedure, however typically even for peripheral procedures the balloon is expanded for less than five minutes. Due to the short duration of contact between the drug coated balloon surface and the blood vessel wall, the balloon coating must exhibit efficient therapeutic agent transfer and/or efficient drug release during inflation. Thus, there are challenges specific to drug delivery via a drug coated or drug eluting balloon that are not present with a drug eluting stent.
Furthermore, conventional drug eluting stent coating processes are not desirable for coating balloons. Such conventional techniques include spraying (air-atomization, ultrasonic, electrostatic, etc.), but might also include roll-coating, dip-coating, spin-coating, vapor deposition, micro-droplet coating, etc. Coating adhesion needs to be robust enough to withstand manufacturing processing, for example, balloon refolding in the dry state, and to survive procedural stresses, for example, passage through the hemostatic valve, guide sheath and tracking to the lesion site when wet. However, coating adhesion also needs to be weak enough such that when the balloon is expanded and pressed into the vessel wall, the drug, drug-polymer, or drug-excipient is transferred. For example, if the coating adhesion is too high, a large majority of the drug remains on the balloon and is still present when the balloon is deflated and removed, even after balloon expansion. Accordingly, coating adhesion needs to be tuned to minimize drug loss during delivery and potential toxic effects from systemic drug exposure, and maximize drug release upon balloon expansion.
The balloon material substrate is fixed and chosen largely for its properties as a dilation balloon. The coating properties can be altered by combining the therapeutic agent with various excipients. Coating structure and physical properties are also dependent on the method of application, e.g., spraying, liquid dispensing, dip-coating, roll coating, etc., and by modulating specific coating parameters, e.g., simultaneous coating-drying, in-line drying, post-coating oven cure, etc. However, the properties of the coating are often dominated by those of the therapeutic agent and excipients, e.g., percentage of drug solids, as it comprises a majority of the coating in order to keep the coating from becoming too thick.
Thus, there remains a need for an efficient and economic method and system for tuning coating on medical devices. The disclosed subject matter addresses this need by performing a plasma treatment to the surface of an expandable member of a medical device prior to coating a therapeutic agent to the expandable member.